DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR
1.17(e), was filed in this application after final rejection. Since this application is eligible for continued
examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the
finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's
submission filed on 08/21/2025 has been entered.
Claims 14-16 are cancelled.
Claims 1-10 are withdrawn.
Claims 11-13 and 17-20 are under current examination.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the
complete set presently being applied to the instant application.
Examiner’s Note
Claim 17, designated as “Previously presented”, recites “polyvinylpyrrolidone” as underlined, indicating that the claim has been amended. The claim is consistent with the previously examined claims filed 01/29/2025; thus, the claim is being treated as “Previously presented”. The Examiner suggests that the underlining of “polyvinylpyrrolidone” be omitted.
Claim Interpretation
The limitation “glass transition (Tg) active pharmaceutical agent (API)” of independent claim 11 and dependent claims 13 and 18 is interpreted as an active pharmaceutical agent that exhibits a glass transition.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 11-13 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (US 2005/0129772 A1, published June 16, 2005; of record), hereafter “Smith”, as evidenced by NIH (“Triacetin” https://pubchem.ncbi.nlm.nih.gov/compound/Triacetin), in view of Rother et al. (EP 2564832 A1, published June 3rd, 2013; of record), hereafter “Rother”.
Regarding instant claim 11, Smith teaches pharmaceutical compositions comprising amorphous (4R)-N-allyl-3-((2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)aminol-4-phenylbutanoyl-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (Compound A), or a pharmaceutically acceptable salt or solvate thereof, their methods of preparation, their use in inhibiting the HIV protease enzyme, and their use in treating HIV-infected mammals (abstract, paragraph [0002]). As compound A is used in treating HIV-infected mammals, it is considered an active pharmaceutical agent. Amorphous compound A exhibits a glass transition temperature (Table 10, paragraph [0193]), and is therefore considered a “glass transition active pharmaceutical agent”.
The compositions of Smith can comprise a solid amorphous dispersion of Compound A and one or more components, collectively referred to as the “matrix” (paragraph [0063]). In an embodiment, the compositions comprise an amorphous form of Compound A and a concentration-enhancing polymer (paragraph [0071]). Compound A and the concentration-enhancing polymer can be combined and formed into a solid amorphous dispersion (paragraph [0103]). The solid amorphous dispersions of Compound A may be made according to any conventional process known to those of ordinary skill in the art (paragraph [0109]), such as a thermal process (paragraph [0110]; one preferred thermal process is an extrusion process where Compound A and the one or more matrix components are dry blended with or without the addition of a plasticizer and fed to a twin-screw extrusion device (paragraph [0113]). Smith teaches that exemplary plasticizers include triacetin (paragraph [0112]). As evidenced by NIH, triacetin is a synonym for glycerol triacetate (pg. 1, “Synonyms”) and is obtained by acetylation of the three hydroxy groups of glycerol (pg. 1, “Description”). The instant specification does not provide a definition of “derivative”; as the triacetin plasticizer of Smith is obtained using glycerol as a precursor via the acetylation of glycerol, it is interpreted to meet the limitation of a glycerol derivative. Glycerol triacetate is also provided as an example of a glycerol derivative in the instant specification (pg. 14, Example 6).
Smith teaches that the concentration-enhancing polymers are capable of further improving the concentration of dissolved drug in an appropriate use environment, and that compositions comprising amorphous Compound A and a concentration-enhancing polymer provide an improved dissolution area-under-the-curve that is greater than that provided by Compound A alone (paragraph [0071]). As the compositions of Smith comprising amorphous Compound A and a concentration-enhancing polymer result in compositions with improved drug dissolution properties, the method of formulating the compositions of Smith is interpreted as a method of improving release of the drug.
Smith teaches that the amount of matrix relative to the amount of drug present in the dispersion of the present invention depends on the characteristics of the matrix and may vary widely from a drug-to-matrix weight ratio of from about 0.01 to about 100 (e.g., 1 wt % drug to 99 wt % drug); preferably, Compound A-to-matrix weight ratio ranges from about 0.1 to about 49 (about 10 wt % drug to about 98 wt% drug) (paragraph [0065]), corresponding to 2 wt% to 90 wt% matrix.
Smith further teaches that the amount of plasticizer used for thermal processes will depend on the melting point of the other matrix components and the desired processing temperature; typically, the ratio of plasticizer to matrix will be 0.01 to 0.5, more typically 0.05 to 0.1 (paragraph [0112]). Using the typical plasticizer to matrix ratio of 0.05 to 0.1, and the preferred matrix amount of 2 wt% to 90 wt%, the teachings of Smith arrive at a wt% of plasticizer in the composition ranging from 0.1 to 9 wt%, as shown in the table below:
Wt.% matrix in composition
Plasticizer to matrix ratio
Wt.% plasticizer in composition
2
0.05
0.1
90
0.1
9
Using the above wt% range of plasticizer in the composition, and the preferred drug amount taught by Smith arrives at a Tg API:plasticizer wt. ratio overlapping that of the instant claims, as shown in the table below. Per MPEP 2144.05: “[i]n the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Wt.% plasticizer in composition
Wt.% drug in composition
Drug to plasticizer ratio (w:w)
0.1
98
980:1
9
10
1.11:1
As Smith teaches that the inclusion of a plasticizer in the matrix can reduce the processing temperature and that the amount of plasticizer used for thermal processes will depend on the melting point of the other matrix components and the desired processing temperature (paragraph [0112]), the amount of plasticizer used and the corresponding ratio of drug to plasticizer could be routinely optimized by one of ordinary skill in the art in order to reach a desired processing temperature.
Further, Rother teaches a pharmaceutical dosage form comprising a solid dispersion of at least one Tg HIV protease inhibitor and at least one pharmaceutically acceptable plasticizer (claims 1 and 14) that is formulated by processing the compositions by melt extrusion and subsequent milling and compression (paragraph [0055]). Preferable plasticizers include triacetin and triethyl citrate (claim 15). Rother exemplifies a formulation in Table 1 that contains 25 wt.% of a combination of HIV protease inhibitors (lopinavir and ritonavir) and 5 wt.% of a plasticizer (exemplifying triethyl citrate), giving a ratio of 5:1. The teachings of Rother indicate to one of ordinary skill in the art that a 5:1 ratio of API:plasticizer is known in the art to be suitable for forming HIV protease inhibitor-plasticizer compositions via thermal extrusion.
Per MPEP 2144.05 II.A, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding instant claim 12, as detailed above, the plasticizer of Smith is taught to be preferably present in the composition in a wt.% range of 0.1 to 9 wt.%, or less than 15% w/w.
Regarding instant claim 13, as noted above, Smith teaches that preferably, the Compound A-to-matrix weight ratio ranges from about 0.1 to about 49 (about 10 wt % drug to about 98 wt % drug) (paragraph [0065]), overlapping the range of the instant claim.
Regarding instant claim 18, as noted above, Compound A of Smith is an inhibitor of the HIV protease enzyme (paragraph [0002]).
Regarding instant claim 19, Smith teaches that the compositions may be administered in combination with an additional agent or agents including HIV protease inhibitors (paragraph [0154]), examples of which include atazanavir (paragraph [0155]); the additional agents may be present in the same formulation as the compositions (paragraph [0169]).
Regarding instant claim 20, Smith teaches that the compositions may be used in a variety of dosage forms, including tablets (paragraph [0152]).
Smith does not teach the inclusion of a plasticizer in the claimed ratio in the method for improving release of a glass transition active pharmaceutical agent with sufficient specificity to anticipate, but rather renders obvious the claimed method. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method of formulating a solid amorphous dispersion taught by Smith to include a plasticizer. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success as Smith teaches that thermal processes such as extrusion are conventional processes for forming solid amorphous dispersions, and it is desirable to keep the processing temperature as low as possible to avoid thermal degradation of the drug (paragraphs [0109]-[0110]); plasticizers can be used in the matrix to reduce processing temperature (paragraph [0112]).
Further, in regards to the amount of the API, plasticizer, and ratio of API to plasticizer, per MPEP 2144.05: “[i]n the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Smith, as evidenced by NIH, in view of Rother as applied to claims 11-13 and 18-20 above, and further in view of Siriwannakij et al. (“Aqueous Dissolution and Dispersion Behavior of Polyvinylpyrrolidone Vinyl Acetate-based Amorphous Solid Dispersion of Ritonavir Prepared by Hot-Melt Extrusion with and without Added Surfactants” Journal of Pharmaceutical Sciences, available online 20 August, 2020, 110, 1480-1494; of record), hereafter “Siriwannakij”.
The teachings of the modified Smith are described above. Smith further teaches that exemplary materials that are suitable for use as a matrix component for thermal processes include both polyvinyl pyrrolidone and copolymers comprising polyvinyl acetate (paragraph [0111]). Smith further teaches that ritonavir is a compound useful as an HIV protease inhibitor that may be useful in combination with the compositions of the invention (paragraph [0155]) and may be present in the same formulation (paragraph [0169]).
The combination of Smith and Rother does not teach that a single polymer is polyvinylpyrrolidone/vinyl acetate.
Siriwannakij teaches the preparation of amorphous solid dispersions of ritonavir-polymer compositions via hot-melt extrusion (pg. 1483, column 2, “Hot-Melt Extrusion”, Table 1). The polymer of Siriwannakij is PVPVA (also known as polyvinylpyrrolidone vinyl acetate; see abstract and pg. 1483, column 1, paragraph 1). Siriwannakij further teaches that amorphous solid dispersions (ASDs) containing PVPVA as the polymeric drug carrier avoid surface-coating by relatively-water insoluble ritonavir which is a major reason for incomplete drug release from ASDs; 80-90% of drug was either dissolved or dispersed even when no additional surfactant was present (pg. 1492, column 2, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art to use the PVPVA taught by Siriwannakij as the polymer in the method for improving release of a glass transition active pharmaceutical agent taught by Smith. One of ordinary skill in the art would have been motivated to do so in order to use a polymer known to avoid surface coating and improve drug release of a poorly water-soluble protease inhibitor from amorphous solid dispersions, as suggested by Siriwannakij. There is a reasonable expectation of success as the method of Smith is taught to use a concentration-enhancing polymer to improve the solubility and bioavailability of a poorly aqueously soluble protease inhibitor (paragraphs [0002], [0004], and [0071]) and formulations can include the protease inhibitor of ritonavir taught by Siriwannakij; Smith further teaches that exemplary materials that are suitable for use as a matrix component for thermal processes include polyvinyl pyrrolidone and copolymers comprising polyvinyl acetate copolymers (paragraph [0111]).
Response to Arguments
Applicants’ arguments filed 08/21/2025 have been fully considered, but are considered unpersuasive.
Regarding the claim rejections under 35 USC § 103, Applicants argue that that the amended claim limitation of a plasticizer being at least one of glycerol or a glycerol derivative is not taught by Smith nor its combination with Rother and Siriwannakij.
This argument is unpersuasive. As set forth in the above rejections, Smith teaches the inclusion of a plasticizer, and that exemplary plasticizers include triacetin (see particularly paragraph [0112]). Rother similarly teaches the use of triacetin as a plasticizer (claims 14-15). As evidenced by NIH, triacetin is a synonym for glycerol triacetate (pg. 1, “Synonyms”) and is obtained by acetylation of the three hydroxy groups of glycerol (pg. 1, “Description”); it is therefore considered to be a glycerol derivative. It is also consistent with the glycerol triacetate provided in the instant specification as an example of a glycerol derivative (pg. 14, Example 6). The Examiner maintains that the teachings of the prior art render the instant claims obvious, as detailed above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611